Large-scale meta-genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types

Elnaz Naderi; Miguel E. Aguado-Barrera; Line M.H. Schack; Leila Dorling; Tim Rattay; Laura Fachal; Holly Summersgill; Laura Martínez-Calvo; Ceilidh Welsh; Tom Dudding; Yasmin Odding; Ana Varela-Pazos; Rajesh Jena; David J. Thomson; Roel J.H.M. Steenbakkers; Joe Dennis; Ramón Lobato-Busto; Jan Alsner; Andy Ness; Chris Nutting; Antonio Gómez-Caamaño; Jesper G. Eriksen; Steve J. Thomas; Amy M. Bates; Adam J. Webb; Ananya Choudhury; Barry S. Rosenstein; Begona Taboada-Valladares; Carsten Herskind; David Azria; David P. Dearnaley; Dirk de Ruysscher; Elena Sperk; Emma Hall; Hilary Stobart; Jenny Chang-Claude; Kim De Ruyck; Liv Veldeman; Manuel Altabas; Maria Carmen De Santis; Marie Pierre Farcy-Jacquet; Marlon R. Veldwijk; Matthew R. Sydes; Matthew Parliament; Nawaid Usmani; Neil G. Burnet; Petra Seibold; R. Paul Symonds; Jens Overgaard; Christian Nicolaj Andreassen; The Radiogenomics Consortium

doi:10.1093/jncics/pkad088

Large-scale meta-genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types

Elnaz Naderi, Miguel E. Aguado-Barrera, Line M.H. Schack, Leila Dorling, Tim Rattay, Laura Fachal, Holly Summersgill, Laura Martínez-Calvo, Ceilidh Welsh, Tom Dudding, Yasmin Odding, Ana Varela-Pazos, Rajesh Jena, David J. Thomson, Roel J.H.M. Steenbakkers, Joe Dennis, Ramón Lobato-Busto, Jan Alsner, Andy Ness, Chris NuttingAntonio Gómez-Caamaño, Jesper G. Eriksen, Steve J. Thomas, Amy M. Bates, Adam J. Webb, Ananya Choudhury, Barry S. Rosenstein, Begona Taboada-Valladares, Carsten Herskind, David Azria, David P. Dearnaley, Dirk de Ruysscher, Elena Sperk, Emma Hall, Hilary Stobart, Jenny Chang-Claude, Kim De Ruyck, Liv Veldeman, Manuel Altabas, Maria Carmen De Santis, Marie Pierre Farcy-Jacquet, Marlon R. Veldwijk, Matthew R. Sydes, Matthew Parliament, Nawaid Usmani, Neil G. Burnet, Petra Seibold, R. Paul Symonds, Jens Overgaard, Christian Nicolaj Andreassen, The Radiogenomics Consortium

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

Abstract

Background: This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity across 4 cancer types (prostate, head and neck, breast, and lung). Methods: A genome-wide association study meta-analysis was performed using 19 cohorts totaling 12 042 patients. Acute standar- dized total average toxicity (STATacute) was modelled using a generalized linear regression model for additive effect of genetic var- iants, adjusted for demographic and clinical covariates (rSTATacute). Linkage disequilibrium score regression estimated shared single-nucleotide variation (SNV-formerly SNP)-based heritability of rSTATacute in all patients and for each cancer type. Results: Shared SNV-based heritability of STATacute among all cancer types was estimated at 10% (SE = 0.02) and was higher for pros- tate (17%, SE = 0.07), head and neck (27%, SE = 0.09), and breast (16%, SE = 0.09) cancers. We identified 130 suggestive associated SNVs with rSTATacute (5.0 × 10^-8 < P < 1.0 × 10^-5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size -0.17; P = 1.7 × 10^-7), which is located near DPPA4, encoding a protein involved in pluripotency in stem cells, which are essential for repair of radiation-induced tissue injury. Gene-set enrichment analysis identified ‘RNA splicing via endonucleolytic cleavage and ligation’ (P = 5.1 × 10^-6, P = .079 corrected) as the top gene set associated with rSTATacute among all patients. In silico gene expression analysis showed that the genes associated with rSTATacute were statistically significantly up-regulated in skin (not sun exposed P = .004 corrected; sun exposed P = .026 corrected). Conclusions: There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future meta-genome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the com- mon causal variants for acute radiotoxicity across cancer types.

Originalsprog	Engelsk
Artikelnummer	pkad088
Tidsskrift	JNCI Cancer Spectrum
Vol/bind	7
Nummer	6
ISSN	2515-5091
DOI	https://doi.org/10.1093/jncics/pkad088
Status	Udgivet - dec. 2023

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10.1093/jncics/pkad088Licens: CC BY-NC

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Naderi, E., Aguado-Barrera, M. E., Schack, L. M. H., Dorling, L., Rattay, T., Fachal, L., Summersgill, H., Martínez-Calvo, L., Welsh, C., Dudding, T., Odding, Y., Varela-Pazos, A., Jena, R., Thomson, D. J., Steenbakkers, R. J. H. M., Dennis, J., Lobato-Busto, R., Alsner, J., Ness, A., ... The Radiogenomics Consortium (2023). Large-scale meta-genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types. JNCI Cancer Spectrum, 7(6), Artikel pkad088. https://doi.org/10.1093/jncics/pkad088

@article{8caabef8f9bc45f5b16e2229c0bd92a9,

title = "Large-scale meta-genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types",

abstract = "Background: This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity across 4 cancer types (prostate, head and neck, breast, and lung). Methods: A genome-wide association study meta-analysis was performed using 19 cohorts totaling 12 042 patients. Acute standar- dized total average toxicity (STATacute) was modelled using a generalized linear regression model for additive effect of genetic var- iants, adjusted for demographic and clinical covariates (rSTATacute). Linkage disequilibrium score regression estimated shared single-nucleotide variation (SNV-formerly SNP)-based heritability of rSTATacute in all patients and for each cancer type. Results: Shared SNV-based heritability of STATacute among all cancer types was estimated at 10% (SE = 0.02) and was higher for pros- tate (17%, SE = 0.07), head and neck (27%, SE = 0.09), and breast (16%, SE = 0.09) cancers. We identified 130 suggestive associated SNVs with rSTATacute (5.0 × 10-8 < P < 1.0 × 10-5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size -0.17; P = 1.7 × 10-7), which is located near DPPA4, encoding a protein involved in pluripotency in stem cells, which are essential for repair of radiation-induced tissue injury. Gene-set enrichment analysis identified {\textquoteleft}RNA splicing via endonucleolytic cleavage and ligation{\textquoteright} (P = 5.1 × 10-6, P = .079 corrected) as the top gene set associated with rSTATacute among all patients. In silico gene expression analysis showed that the genes associated with rSTATacute were statistically significantly up-regulated in skin (not sun exposed P = .004 corrected; sun exposed P = .026 corrected). Conclusions: There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future meta-genome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the com- mon causal variants for acute radiotoxicity across cancer types.",

author = "Elnaz Naderi and Aguado-Barrera, {Miguel E.} and Schack, {Line M.H.} and Leila Dorling and Tim Rattay and Laura Fachal and Holly Summersgill and Laura Mart{\'i}nez-Calvo and Ceilidh Welsh and Tom Dudding and Yasmin Odding and Ana Varela-Pazos and Rajesh Jena and Thomson, {David J.} and Steenbakkers, {Roel J.H.M.} and Joe Dennis and Ram{\'o}n Lobato-Busto and Jan Alsner and Andy Ness and Chris Nutting and Antonio G{\'o}mez-Caama{\~n}o and Eriksen, {Jesper G.} and Thomas, {Steve J.} and Bates, {Amy M.} and Webb, {Adam J.} and Ananya Choudhury and Rosenstein, {Barry S.} and Begona Taboada-Valladares and Carsten Herskind and David Azria and Dearnaley, {David P.} and {de Ruysscher}, Dirk and Elena Sperk and Emma Hall and Hilary Stobart and Jenny Chang-Claude and {De Ruyck}, Kim and Liv Veldeman and Manuel Altabas and {De Santis}, {Maria Carmen} and Farcy-Jacquet, {Marie Pierre} and Veldwijk, {Marlon R.} and Sydes, {Matthew R.} and Matthew Parliament and Nawaid Usmani and Burnet, {Neil G.} and Petra Seibold and Symonds, {R. Paul} and Jens Overgaard and Andreassen, {Christian Nicolaj} and {The Radiogenomics Consortium}",

year = "2023",

month = dec,

doi = "10.1093/jncics/pkad088",

language = "English",

volume = "7",

journal = "JNCI Cancer Spectrum",

issn = "2515-5091",

publisher = "Oxford University Press",

number = "6",

}

Naderi, E, Aguado-Barrera, ME, Schack, LMH, Dorling, L, Rattay, T, Fachal, L, Summersgill, H, Martínez-Calvo, L, Welsh, C, Dudding, T, Odding, Y, Varela-Pazos, A, Jena, R, Thomson, DJ, Steenbakkers, RJHM, Dennis, J, Lobato-Busto, R, Alsner, J, Ness, A, Nutting, C, Gómez-Caamaño, A, Eriksen, JG, Thomas, SJ, Bates, AM, Webb, AJ, Choudhury, A, Rosenstein, BS, Taboada-Valladares, B, Herskind, C, Azria, D, Dearnaley, DP, de Ruysscher, D, Sperk, E, Hall, E, Stobart, H, Chang-Claude, J, De Ruyck, K, Veldeman, L, Altabas, M, De Santis, MC, Farcy-Jacquet, MP, Veldwijk, MR, Sydes, MR, Parliament, M, Usmani, N, Burnet, NG, Seibold, P, Symonds, RP, Overgaard, J , Andreassen, CN & The Radiogenomics Consortium 2023, 'Large-scale meta-genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types', JNCI Cancer Spectrum, bind 7, nr. 6, pkad088. https://doi.org/10.1093/jncics/pkad088

Large-scale meta-genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types. / Naderi, Elnaz; Aguado-Barrera, Miguel E.; Schack, Line M.H. et al.
I: JNCI Cancer Spectrum, Bind 7, Nr. 6, pkad088, 12.2023.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

TY - JOUR

T1 - Large-scale meta-genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types

AU - Naderi, Elnaz

AU - Aguado-Barrera, Miguel E.

AU - Schack, Line M.H.

AU - Dorling, Leila

AU - Rattay, Tim

AU - Fachal, Laura

AU - Summersgill, Holly

AU - Martínez-Calvo, Laura

AU - Welsh, Ceilidh

AU - Dudding, Tom

AU - Odding, Yasmin

AU - Varela-Pazos, Ana

AU - Jena, Rajesh

AU - Thomson, David J.

AU - Steenbakkers, Roel J.H.M.

AU - Dennis, Joe

AU - Lobato-Busto, Ramón

AU - Alsner, Jan

AU - Ness, Andy

AU - Nutting, Chris

AU - Gómez-Caamaño, Antonio

AU - Eriksen, Jesper G.

AU - Thomas, Steve J.

AU - Bates, Amy M.

AU - Webb, Adam J.

AU - Choudhury, Ananya

AU - Rosenstein, Barry S.

AU - Taboada-Valladares, Begona

AU - Herskind, Carsten

AU - Azria, David

AU - Dearnaley, David P.

AU - de Ruysscher, Dirk

AU - Sperk, Elena

AU - Hall, Emma

AU - Stobart, Hilary

AU - Chang-Claude, Jenny

AU - De Ruyck, Kim

AU - Veldeman, Liv

AU - Altabas, Manuel

AU - De Santis, Maria Carmen

AU - Farcy-Jacquet, Marie Pierre

AU - Veldwijk, Marlon R.

AU - Sydes, Matthew R.

AU - Parliament, Matthew

AU - Usmani, Nawaid

AU - Burnet, Neil G.

AU - Seibold, Petra

AU - Symonds, R. Paul

AU - Overgaard, Jens

AU - Andreassen, Christian Nicolaj

AU - The Radiogenomics Consortium

PY - 2023/12

Y1 - 2023/12

N2 - Background: This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity across 4 cancer types (prostate, head and neck, breast, and lung). Methods: A genome-wide association study meta-analysis was performed using 19 cohorts totaling 12 042 patients. Acute standar- dized total average toxicity (STATacute) was modelled using a generalized linear regression model for additive effect of genetic var- iants, adjusted for demographic and clinical covariates (rSTATacute). Linkage disequilibrium score regression estimated shared single-nucleotide variation (SNV-formerly SNP)-based heritability of rSTATacute in all patients and for each cancer type. Results: Shared SNV-based heritability of STATacute among all cancer types was estimated at 10% (SE = 0.02) and was higher for pros- tate (17%, SE = 0.07), head and neck (27%, SE = 0.09), and breast (16%, SE = 0.09) cancers. We identified 130 suggestive associated SNVs with rSTATacute (5.0 × 10-8 < P < 1.0 × 10-5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size -0.17; P = 1.7 × 10-7), which is located near DPPA4, encoding a protein involved in pluripotency in stem cells, which are essential for repair of radiation-induced tissue injury. Gene-set enrichment analysis identified ‘RNA splicing via endonucleolytic cleavage and ligation’ (P = 5.1 × 10-6, P = .079 corrected) as the top gene set associated with rSTATacute among all patients. In silico gene expression analysis showed that the genes associated with rSTATacute were statistically significantly up-regulated in skin (not sun exposed P = .004 corrected; sun exposed P = .026 corrected). Conclusions: There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future meta-genome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the com- mon causal variants for acute radiotoxicity across cancer types.

AB - Background: This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity across 4 cancer types (prostate, head and neck, breast, and lung). Methods: A genome-wide association study meta-analysis was performed using 19 cohorts totaling 12 042 patients. Acute standar- dized total average toxicity (STATacute) was modelled using a generalized linear regression model for additive effect of genetic var- iants, adjusted for demographic and clinical covariates (rSTATacute). Linkage disequilibrium score regression estimated shared single-nucleotide variation (SNV-formerly SNP)-based heritability of rSTATacute in all patients and for each cancer type. Results: Shared SNV-based heritability of STATacute among all cancer types was estimated at 10% (SE = 0.02) and was higher for pros- tate (17%, SE = 0.07), head and neck (27%, SE = 0.09), and breast (16%, SE = 0.09) cancers. We identified 130 suggestive associated SNVs with rSTATacute (5.0 × 10-8 < P < 1.0 × 10-5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size -0.17; P = 1.7 × 10-7), which is located near DPPA4, encoding a protein involved in pluripotency in stem cells, which are essential for repair of radiation-induced tissue injury. Gene-set enrichment analysis identified ‘RNA splicing via endonucleolytic cleavage and ligation’ (P = 5.1 × 10-6, P = .079 corrected) as the top gene set associated with rSTATacute among all patients. In silico gene expression analysis showed that the genes associated with rSTATacute were statistically significantly up-regulated in skin (not sun exposed P = .004 corrected; sun exposed P = .026 corrected). Conclusions: There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future meta-genome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the com- mon causal variants for acute radiotoxicity across cancer types.

UR - http://www.scopus.com/inward/record.url?scp=85178100666&partnerID=8YFLogxK

U2 - 10.1093/jncics/pkad088

DO - 10.1093/jncics/pkad088

M3 - Journal article

C2 - 37862240

AN - SCOPUS:85178100666

SN - 2515-5091

VL - 7

JO - JNCI Cancer Spectrum

JF - JNCI Cancer Spectrum

IS - 6

M1 - pkad088

ER -

Large-scale meta-genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types

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